Boirie1
1 Université Clermont Auvergne, CHU Clermont-Ferrand, INRAE, UNH, F-63000 Clermont—Ferrand, France
2 Université Clermont Auvergne, INRAE, UNH, F-63000 Clermont—Ferrand, France
INTRODUCTION
Muscle erosion, which begins after the age of 50 years, is one of the most important factors of disability in older people, but it may also occur early in life in case of chronic disease [1]. The cumulative decline in muscle mass reaches 40% from 20 to 80 years. The magnitude of this phenomenon as a public health problem is now well established as there has been a lot of epidemiological studies and meta‐analysis focusing on the decrements of strength and muscle mass with advancing age. So, sarcopenia has been recognized as a specific disease with an International Classification of Diseases (ICD) code (M62.84) [2]. The reduction in muscle mass and strength provokes an impaired mobility and increased risk for falls and fall‐related fractures. In addition, muscle loss is associated with a decrease in overall physical activity levels with subsequent metabolic alterations such as obesity, insulin resistance, and a reduction in bone density in older persons. Sedentary individuals, subjects with poor protein intakes, low vitamin D and low testosterone levels, and those suffering from debilitating or inflammatory diseases are at greater risks of sarcopenia. As older person population increases around the world, the involuntary loss of muscle mass with aging will become a major health problem in years to come, from a European prevalence of 10.9 million in 2016 to 18.7 million in 2045 [3].
Sarcopenia is due predominantly to the atrophy of skeletal muscle fibers, mainly type II fibers [4]. This results in a relative elevation in type I fiber density related to a supposed preservation of muscle endurance and a reduction in muscle strength. On a metabolic point of view, muscle size, function, and composition are closely regulated by muscle protein turnover rate. Consequently, the age‐related loss of muscle proteins is a consequence of an imbalance between protein synthesis and degradation rates (Figure 5.1); whereas, basal muscle protein synthesis and breakdown rates appear to be unaffected by age [5, 6], the muscle protein synthetic response to the main anabolic stimuli, i.e. food intake and physical activity, appears to be blunted in older individuals [7–9]. This anabolic resistance is now considered to be a key factor contributing to progressive loss of skeletal muscle mass throughout our lifespan. Other factors such as neurodegenerative processes with loss of alpha motor neurons in the spinal column, dysregulation of anabolic hormone (insulin, growth, and sex hormones) and cytokine productions, modifications in the response to inflammatory events, inadequate nutritional intakes, and sedentarism also participate in muscle loss during aging.
The determinants of sarcopenia include likely both genetic and environmental factors, with a complex series of poorly understood interactions [10]. Likewise it is possible that epigenetic events may influence muscle fiber type evolution [11]. In fact, it is still unknown whether muscle loss of aged people is an inevitable condition of aging per se, or if illnesses, inappropriate nutrition, sedentarism, and other lifestyle habits are major causes of sarcopenia. Currently, as the pathophysiology of sarcopenia is still poorly understood and identified in clinical practice, interventions to either prevent, retard, or reverse this condition are still limited: physical exercise has a positive impact on muscle mass, function, and performance in healthy subjects aged over 60 years with very large variations in response to the dietary supplementation protocols [12–14].
Figure 5.1 Regulation of muscle protein mass.
EVIDENCES FOR A ROLE FOR NUTRITION IN SARCOPENIA
“Anabolic resistance” of skeletal muscle to nutrition in older persons
Many authors have argued that muscle loss in older persons partly depends upon inadequate nutritional intake and/or an impaired response of skeletal muscle to nutrients, e.g. amino acids [13, 15]. By using femoral arterio‐venous balance and biopsies of vastus lateralis, the rates of muscle protein synthesis and breakdown have been measured in response to oral or intravenous infusions of amino acid mixture in young and older persons [16, 17]. When amino acids are infused intravenously, a significant increase in amino acid delivery to the leg, amino acid transport, and muscle protein synthesis is reported irrespective of age [16]. So, although protein breakdown was not modified during amino acid infusion, a positive net balance of amino acids across the muscle was achieved. These data suggest that despite an age‐related decline in muscle mass, muscle protein anabolism can be stimulated by high amino acid availability in older persons [16]. Muscle protein turnover and amino acid transport in healthy young and older people were also determined during an oral administration of an amino acid mixture. As already shown by Boirie et al. for leucine [18], amino acid first‐pass splanchnic extraction of phenylalanine was significantly higher in older persons during ingestion of amino acids, but the delivery to the leg increased to the same extent in both groups. In addition, amino acid transport into muscle cells, muscle protein synthesis, and net balance increased similarly in both the young and older persons [17]. Thus, despite an increased splanchnic extraction, muscle protein anabolism can be stimulated by oral amino acids in older as well as in young subjects as far as the dietary protein intakes or the amount of amino acid mixture administered is high enough to induce a sufficient amino acid availability for skeletal muscles. Interestingly, muscle protein synthesis increased to the same extent after an oral intake of either balanced amino acids or essential amino acids (EAAs) only in healthy older persons [19], suggesting that nonessential amino acids may not be required to stimulate muscle protein anabolism in older adults, although specific studies on which and how much of these EAAs has to be performed. From these studies it seems that the amount of amino acids/protein intake is crucial for triggering protein synthesis. Indeed, it was demonstrated that a smaller amount of protein during meal intake was not able to stimulate muscle protein synthesis as efficiently as higher doses [20]. This concept of a limited response to feeding was already demonstrated in animal studies involving old rodents [21, 22]. When amino acids and glucose are administered either orally or intravenously during an euglycemic hyperinsulinemic clamp [8, 23] an increased amino acid delivery and transport into the muscle and a decreased muscle protein breakdown occurs in both groups. However, the stimulation of muscle protein synthesis in the young subjects was not depicted in older persons despite the elevation in plasma amino acids and an even higher insulinemia [8, 23]. More recently, an impaired capacity to increase muscle protein synthesis rates in response to protein intake was confirmed in large cohorts of healthy young and older men [9]. Interestingly, the response of whole body protein breakdown was lower in older persons in response to insulin or to the meal [24–26]. The adaptation of muscle protein anabolism to hyperaminoacidemia and hyperinsulinemia seems to be due to an impaired response to insulin as demonstrated by direct infusion into the arterial side of the muscle area [27]. When specific muscle protein fractions within the skeletal muscle were separated, it was shown that the mitochondrial proteins were particularly affected by the age‐related insulin resistance [8, 28]. Investigations from Elena Volpi's group have indicated that the blunted response of protein synthesis in healthy older persons was the result of a decreased adaptation of leg blood flow to insulin [29]. Indeed blood flow is a crucial determinant of amino acid delivery and of the protein synthesis process through amino acids transport [30]. When blood flow was restored by using nitroprussiate in older persons, muscle protein synthesis was also normalized [31]. These studies lead us to open the question of muscle sensitivity to hormones like insulin or to substrates like amino acids, suggesting that a threshold needs to be reached to induce muscle protein synthesis and that this threshold may be higher in the case of inflammation (Figure 5.2). Previous studies have shown that reducing inflammation
